NEW DEVELOPMENTS IN OSTEOPOROSIS
Prof Stephen Hough
MBChB; Hons BSc; MMed; FCP(SA); MD
Head: Endocrine Unit and
Chairman: Department of Medicine
Faculty of Health Sciences
University of Stellenbosch and
The Tygerberg Academic Hospital
Introduction
R
ecent developments in osteoporosis involve a reassessment of our conceptual
understanding of its definition and therefore approach to diagnosis, as well as
technological advances in acute and long-term management. Technological
advances include the introduction of new anabolic agents like teriparatide and
strontium ranelate to treat patients with severe osteoporosis, more evidence-based
data from randomised controlled trials on the efficacy and safety of known boneactive agents, and new techniques like percutaneous kyphoplasty, to manage acute
vertebral fractures.
Conventional definitions of osteoporosis
O
steoporosis was historically defined on a histological and radiological basis.
In the mid nineties a working group of the World Health Organisation (WHO)
adopted a largely densitometric definition, regarding osteoporosis as a
systemic skeletal disease characterised by a low bone mass and micro-architectural
deterioration of bone tissue with a consequent increase in bone fragility and
susceptibility to fracture. Since bone mass accounts for up to 70% of the variance
in bone strength in vitro, and is the only variable that can be accurately determined,
its measurement (as bone mineral density, BMD) currently embodies the practical
basis for the diagnosis of osteoporosis.
While the 4 diagnostic categories of the WHO classification, which defines
osteoporosis as a BMD of at least 2.5 standard deviations (SD) below the average
for a 30yr old Caucasian female, have provided a practical basis to identify those at
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risk of sustaining a fracture, we need to take cognisance of its limitations viz (i) a
single BMD measurement lacks sensitivity and up to 50% of patients with a known
osteoporotic fracture may have a normal BMD, (ii) the WHO criteria are based on
data obtained from white, postmenopausal women, employing dual energy x-ray
absorptiometry (DEXA) of the axial skeleton (spine and hip), and cannot be
extrapolated to other populations (males, young individuals, Blacks) or other
techniques to measure BMD (e.g. QCT, ultrasound), (iii) causes of a low BMD other
than osteoporosis (e.g. primary hyperparathyroidism, osteomalacia) are not
considered, (iv) extraskeletal risk factors for fracture (e.g. propensity for falls) are
not addressed, and (v) qualitative bone changes are not assessed.
New definitions of osteoporosis
A
lthough still recognising the importance of BMD, the most recent National
Institutes of Health (NIH) consensus statement defines osteoporosis as “a
skeletal disorder characterised by compromised bone strength that results in
an increased risk of fracture.”
The concept of bone strength has evolved to
integrate those traditional measures of bone quantity (e.g. BMD) with more recently
examined components of bone quality viz (i) macro-architecture (bone size and
geometry), (ii) micro-architecture (cortical thinning, porosity; trabecular size,
number, connectivity), (iii) bone turnover, and (iv) material properties of bone (e.g.
mineralisation, micro-fracture, collagen cross-linking).
BMD–independent determinants of bone strength and fracture
A
lthough bone quality is difficult to assess clinically, a number of BMDindependent risk factors are now recognised, which can aid the physician to
identify those at risk.
Age is one of the best-known risk factors for
osteoporotic fracture, independent of BMD, and various changes in bone quality
have been proposed to explain this observation. Up to 80% of the variation in peak
BMD is determined genetically; a genetic predisposition to fracture, independent of
BMD, has, however, recently been demonstrated. Polymorphisms in a number of
genes (e.g. those encoding the oestrogen receptor, collagen, growth factors etc.)
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have been proposed to explain this observation. Ethnicity affords another example.
In South Africa, the incidence of osteoporosis in White, Asian and Mixed Race
populations appears to be similar to incidence rates in developed countries.
Osteoporotic fractures are, however, 10 times less prevalent in our Black
populations, which is also the case in the USA. Whereas the lower prevalence of
fractures in Afro-Americans is readily explained on the basis of an approximate 15%
higher BMD in this population compared with Caucasians, vertebral BMD in Black
and White South Africans appears to be quite comparable!
In large osteoporosis drug trials of bisphosphonates (FIT, VERT), selective oestrogen
receptor modulators (MORE) and calcitonin (PROOF), a history of vertebral fractures
was shown to increase the risk of a subsequent fracture 3-5 fold. Moreover, these
studies revealed no correlation between changes in BMD and the degree of fracture
risk reduction, following drug therapy.
A low body mass and bone toxins (e.g.
glucocorticoids, alcohol, tobacco) are further examples of BMD-independent
determinants of bone strength.
A high bone turnover may result in trabecular
perforation and decreased interconnectedness, which markedly increase the
likelihood of fracture, independent of BMD. Recently, animal studies have suggested
that a markedly suppressed bone turnover may also predispose to fracture, but
evidence-based data in patients are lacking. Finally, the importance of extraskeletal
factors should not be ignored – falls, especially sideways falls, are incriminated in
more than 80% of femoral neck fractures.
Diagnostic criteria vs intervention thresholds
T
he diagnostic categories developed by the WHO for postmenopausal
Caucasian women should not be regarded as intervention thresholds for all.
The need to treat should not depend on the establishment of a largely BMD
based diagnosis alone, but should also be determined by (i) the nature of the
disease (presence of fragility fractures, abnormal bone turnover, severity and rate of
bone loss etc), (ii) the patient profile (age, gender, life expectancy, general health,
clinical risk factors/causes of secondary osteoporosis) and (iii) the cost-effectiveness
and side-effects of available treatment.
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The evaluation of BMD-independent risk factors is particularly important in those
cases where spine or hip BMD values are not markedly decreased and do not fall
within the so-called osteoporosis range ( 2.5 SD below peak BMD).
Moreover,
certain forms of the disease, for example glucocorticoid-induced osteoporosis
(GCOP), are known to fracture at higher BMD values – an intervention threshold of 
1.5 SD below peak BMD has been recommended for GCOP, whereas the British
Rheumatology Society recommends bone active drugs in all subjects over age 65
years who receive glucocorticoids for longer than 3 months.
A known fragility
fracture, which is probably the single strongest predictor for future fractures, would
constitute another indication for treatment, regardless of the BMD.
In this regard, the principles of osteoporosis management do not differ
fundamentally from that of most other chronic degenerative diseases.
Although
diagnostic cut-off values for an increased blood pressure or plasma cholesterol have
been clearly established, intervention thresholds and the nature of therapy are
determined by very similar co-morbid factors. Clearly health care workers, as well
as medical-aid funders, need to take cognisance of this paradigm shift in our
approach to the management of patients with osteoporosis.
Non-pharmacological measures to improve bone strength and
prevent fractures
T
hese include a balanced diet rich in dairy, physical exercise, limiting alcohol
consumption, the avoidance of smoking and bone toxic drugs, and the
prevention of falls.
Particularly in older patients, the comprehensive
assessment of falls and appropriate preventive measures may be more important
than pharmacological intervention to reduce the risk of fractures (i) Muscle
weakness (the term “sarcopenia” was coined to emphasise the importance of this
risk factor) and disturbances in balance and gait should be assessed, and exercise
programmes implemented, (ii) Medication, particularly sedatives and major
tranquillisers, is the single most important reversible risk factor for falls in the
elderly. Antidepressants, antihypertensives, hypoglycaemic agents and alcohol may
also predispose. Other important potentially reversible risk factors include postural
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and postprandial hypotension, visual impairment, vertigo and drop attacks, (iii)
Environmental safety should be ensured.
environment related.
Up to 40% of falls are accident or
The most important risk factors are objects that may be
tripped over, slippery surfaces, inappropriate furniture, high-heelded shoes and poor
lighting, (iv) Previous falls (especially side-ways falls) should be assessed and the
use of external hip protectors considered.
Drugs used to treat osteoporosis
T
hese are conventionally classified as antiresorptive agents and those which
stimulate bone formation. Some drugs have complex actions on bone. A
comprehensive review of these drugs is beyond the scope of this update,
which will largely focus on recent developments in antiresorptive therapy and on the
introduction of new anabolic agents to treat osteoporosis.
Antiresorptive Drugs
Calcium and Vitamin D
Calcium supplementation and prophylactic doses of vitamin D (400-800 IU per day)
cause a modest, but significant improvement in BMD and reduction in risk of
vertebral and non-vertebral fractures. Supplementation is recommended, especially
in the elderly, the institusionalised, and those with a negative calcium balance and
secondary hyperparathyroidism who are at risk of sustaining a hip fracture.
Evidence for the use of pharmacological doses of vitamin D, as well as the use of
vitamin D metabolites like calcitriol is unconvincing. Their use in the management of
osteoporosis is further limited by the risk of hypercalcaemia and hypercalciuria, and
the need for regular monitoring.
Hormone Replacement Therapy
Hormone replacement theraphy (HRT), employing oestrogen plus progestin (EPHT)
or oestrogen alone (EHT), was previously regarded as the gold standard for the
prevention and treatment of osteoporosis.
Although initially based on data from
observational studies, the large randomised, controlled Women’s Health Initiative
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(WHI) recently demonstrated a significant reduction in vertebral (35%), hip (33%)
and total fractures (25%), with both EPHT and EHT. These benefits were, however,
outweighed by an increase of 40% in strokes (both EPHT and EHT), 50-100% in
trombo-embolism (EPHT and EHT), 26% in breast cancer (EPHT only) and 26% in
cardiovascular events (EPHT only).
Although the absolute number of patients
adversely effected (as opposed to the relative risk) was small, total mortality
unchanged, and prolonged exposure (>5 years) required to result in side-effects,
this study disproved a cardioprotective effect of both EPHT as well as EHT,
previously suggested by observational data. HRT remains the only effective
treatment for troublesome vasomotor and urogenital symptoms of the menopause.
It may also alleviate emotional lability, but does not prevent Alzheimer’s disease and
may in fact increase the incidence of dementia in the elderly.
HRT remains a cost-effective method to prevent and treat osteoporosis.
Unlike
many antiresorptive drugs, HRT appears to be highly effective in low-risk subjects,
including those with only a modest decrease in BMD. Rapid, “catch-up” bone loss,
however, occurs after HRT is discontinued. Given the potential adverse extraskeletal
effects of HRT following prolonged use, it is best reserved for the relative short-term
(< 5 years) stabilisation of bone strength in patients younger than 60 years –
ideally, in those who also have troublesome menopausal symptoms. Once stopped,
consideration should be given to its replacement with an alternative agent.
Selective oestrogen receptor modulators (SERMS)
Raloxifene is a SERM which has oestrogen agonist actions on the skeleton and lipid
profile, yet acts as an oestrogen antagonist on the breast and endometrium. In the
MORE study of 7705 postmenopausal women, raloxifene decreased vertebral
fractures by 49% after 4 years, despite a very modest increase in BMD of only 3%.
Although the risk of non-vertebral fractures was not altered, a reanalysis of the
MORE data demonstrated a significant 47% decrease in non-vertebral fractures in
those patients with severe (SQ grade 3) vertebral fractures. Raloxifene decreased
the risk of vertebral fractures in both osteoporotic and osteopenic patients.
Raloxifene has been shown to decrease the risk of breast cancer by 62-84% and has
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no effect on the endometrium.
Adverse events include an increase in thrombo-
embolism, hot flushes and leg cramps. Unlike EPHT, raloxifene does not increase
the risk of cardiovascular disease, and may in fact be cardioprotective in patients at
high risk of cardiovascular disease. While studies like the RUTH and CORE continue
to generate data on raloxifene, trials on other SERMS, including lasofoxifene and
arzoxifene are under way.
Bisphosphonates
The amino-bisphosphonates (alendronate, risedronate, pamidronate, zoledronate)
are analogues of pyrophosphate which decrease bone resorption by reducing
osteoclast recruitment and function, and inducing osteoclast apoptosis, resulting in a
5-8% increase in spine BMD and a 3-6% increase in femoral BMD.
The
antiresorptive effects of the bisphosphonates are ascribed, at least in part, to their
ability to inhibit rate-limiting enzymes (e.g. FPP-synthase) in the mevalonate
pathway. Large randomised controlled trials employing alendronate and risedronate
have documented a significant 40-60% reduction in risk of both vertebral and nonvertebral (including hip) fractures. Bisphosphonates are also effective in the
treatment of glucocorticoid induced and male osteoporosis.
Fracture reduction is a function of both increased BMD and reduced bone-turnover.
The latter effect presumably explains the reduced fracture risk demonstrated within
6 months of starting risedronate therapy. Unlike HRT, bisphosphonates persist in
the skeleton for months to years, which results in a prolonged action.
Large
differences exist amongst the bisphosphonates in their ability to suppress FPPsynthase activity, their binding affinity to bone tissue, and their accumulation in the
skeleton.
suppression.
These factors ultimately determine the degree of bone-turnover
The first 10 year’s experience of alendronate treatment for
osteoporosis was recently published.
Although the increase in BMD was most
pronounced during the first few years of therapy, the reduction in fracture risk
appeared to persist.
Oversuppression of bone turnover after prolonged
administration has raised concerns in animal experiments employing large doses of
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bisphosphonates, but is not supported by current clinical data, although further
studies are required.
Bisphosphonates are poorly absorbed from the gut and may cause upper
gastrointestinal side-effects.
Daily dose regimens have largely been replaced by
once-weekly schedules, and much research is currently focussing on the
development of regimens which range from monthly to even yearly administration.
Calcitonin
This naturally occurring hormone has a rapid, but short lived antiresorptive effect.
Injectable and nasal spray preparations are available.
Fracture efficacy data are
largely limited to the PROOF study, employing 1255 osteoporotic women, which
showed a negligible increase in BMD, yet a 36% reduction in new vertebral fractures
with a dose of 200 IU calcitonin daily – no significant decrease in fracture risk was,
however, observed with 100 or 400 IU per day. Calcitonin has a central, opiatemediated analgesic effect and has been recommended for the management of
painful acute vertebral fractures. Until more evidence-based fracture efficacy data
become available, it’s long-term use should be reserved for those patients who
cannot tolerate other antiresorptive agents.
Anabolic Agents
W
hile the mainstay of current therapies for osteoporosis is the antiresorptive
agents discussed above, these drugs reduce but do not eliminate fracture
risk, and do not restore lost bone structure. Anabolic agents have the
potential to increase BMD, restore micro-architecture and restore fracture risk to a
greater extent than the antiresorptives. Fluoride was the first anabolic agent to be
used in the treatment of osteoporosis. Although a marked increase in BMD followed
the administration of fluoride, this never related to a significant decrease in fracture
risk. Growth hormone, IGF, and more recently the lipid lowering statins have been
proposed, but bothersome side-effects and inability to target these agents to the
skeleton have limited their use. Anabolic steroids and calcitriol may have modest
anabolic effects on bone, but their utility is also limited by adverse effects. More
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recently, strontium ranelate and parathyroid hormone (PTH) have emerged as
promising osteo-anabolic agents.
Teriparatide (PTH1-34)
Intermittent, low-dose PTH administration causes rapid stimulation of bone
formation resulting in a marked increase in bone mass, size and strength, as well as
improvement in trabecular micro-architecture and cortical geometry.
Following a
number of smaller studies, the results of a large randomised placebo-controlled trial
involving 1637 women with postmenopausal osteoporosis were recently published.
Compared with placebo, daily subcutaneous injection of hPTH (1-34), for as little as
21 months, increased lumbar BMD by 9-13% and femoral BMD by 3-6%, and
reduced the risk of spine and non-vertebral fractures by 65% and 40% respectively.
Favourable results of PTH on BMD and biomarkers of bone turnover have also been
reported in male and glucocorticoid-induced osteoporosis.
Side-effects of teriparatide have been limited to occasional nausea, headaches and
leg cramps. Mild hypercalcaemia occurs in up to 10% of patients receiving 20µg
PTH daily and serum uric acid levels may increase by 20%, but renal stones and
clinical gout are not thought to be more prevalent.
Of some concern is the
tumorigenic potential of PTH. Long-term studies with high-dose PTH, administered
to 6-week old Fisher 344 rats, have demonstrated a dose-related increased risk of
osteogenic sarcoma. This effect is consistent with life-long exposure, in a growing
rodent, to high-dose PTH and is unlikely to have relevance to human bone
physiology.
Shorter or lower dose exposure to PTH has not resulted in the
development of osteosarcomas or other bone tumours. All primate studies have
failed to show a similar association and osteogenic sarcomas do not occur with
increased frequency in patients with primary hyperparathyroidism or from any of the
clinical trials performed in over 2500 patients treated with PTH (1-34) for up to 3
years. It is, therefore, reasonable to conclude that PTH is safe in human subjects,
although on-going safety data need to be collated.
Teriparatide has recently become available in South Africa. Given its high cost, both
the manufacturer and local funders approached the National Osteoporosis
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Foundation (NOFSA) to provide guidelines on its use, resulting in the publication of a
position paper. Whereas many potential indications for its use may exist (e.g. very
low prevalent BMD, high fracture risk), NOFSA recommends that teriparatide should
be reserved for patients with severe, established osteoporosis i.e. (1) a low BMD and
2 or more prevalent fractures, or (2) failed anti-resorptive therapy – i.e. after
adhering to adequate anti-resorptive therapy for at least 12 months, the patient
experiences: (i) an incident fragility fracture, or (ii) unacceptable rate of bone loss
(e.g. a decrease in vertebral BMD of  5% per annum) as documented in 2 or more
consecutive follow-up BMD measurements.
A number of contra-indications have been suggested as well as the recommendation
that 20µg teriparatide per day be used, for no longer than 18 months. All patients
should be subjected to a full clinical and laboratory work-up to confirm a diagnosis
of osteoporosis and to rule out other causes of a low BMD (primary
hyperparathyroidism, osteomalacia), rule out causes of secondary osteoporosis
which may require treatment in own right, evaluate the severity of the disease, and
assess compliance and adherence to prior antiresorptive therapy for osteoporosis.
Given recent reports that concurrent use of PTH and potent antiresorptive drugs like
alendronate may ameliorate the anabolic effects of PTH, concomitant treatment of
teriparatide plus antiresorptive agents is not recommended.
Careful clinical and
laboratory follow-up of all subjects are required and following completion of the 18month course of teriparatide therapy, treatment with a potent antiresorptive agent
like a bisphosphonate is recommended, to preserve bone mass gained.
Strontium ranelate
Strontium ranelate has been shown to increase osteoblast proliferation and collagen
synthesis, and to decrease osteoclast replication and activity in vitro. Bone histology
has confirmed the dual action of this drug, increasing bone formation and decreasing
resorption.
Animal studies show an increase in BMD, bone size and strength
following strontium ranelate administration.
Two large RCTs have recently been published.
The SOTI trial employed 1649
women, average age 69yr, with either osteoporosis or osteopenia. After 3 years,
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strontium ranelate significantly increased biomarkers of bone formation and
decreased parameters of resorption, resulting in an increase in lumbar BMD of 14%,
and a 41-52% reduction of new spine fractures.
Quantitative bone histology
revealed no evidence of a mineralisation defect.
The TROPOS trial studied 5091 elderly (76yr) women with an average femoral neck
T-score of –3.1, for 3 years. Femoral BMD increased by 8% and the incidence of hip
fractures was reduced by 36%. Both the SOTI and TROPOS trials demonstrated
excellent adherence to therapy (83%) and no significant adverse effects. Strontium
blood levels can be readily measured to monitor therapy.
This drug will probably be launched in South Africa during 2005 and clearly holds
much promise.
Acute management of symptomatic vertebral fractures
T
raditional management of the acute painful vertebral fracture consists of
analgesia, bedrest with physical support such as a corset, and gradual
mobilisation.
There is, however, no consensus as to the best treatment.
Strong analgesics like the opiates should be used for short periods only.
Non-
steroidal anti-inflammatory drugs have been shown in some studies to suppress
bone formation and fracture healing.
Tricyclic antidepressants (to lower pain
threshold and perception) and some muscle relaxants may predispose to falls.
Calcitonin has central analgesic properties and two recent studies have reported the
use of intravenous bisphosphonates in patients following acute vertebral fracture.
Results were encouraging, but require further study.
Prolonged physical immobilisation and the use of a corset is generally discouraged,
since it is thought to promote bone loss and muscle wasting. The use of specialised
corsets which cause abdominal compression and an improvement in posture may,
however, provide a viable option. Employing such a new spinal orthosis, a recent
RCT documented a significant 40% decrease in pain, an 11% decrease in the angle
of kyphosis, and surprisingly, a 73% increase in back extensor strength and a 58%
increase in abdominal flexor strength. Transcutaneous electrical nerve stimulation
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(TENS), intercostal nerve blocks, acupuncture and implanted devices employing the
“gate-theory” of chronic pain control offer acceptable alternatives.
Vertebral kyphoplasty
Conventional therapy of vertebral fractures allows the bone to heal in its fractured or
deformed state.
This may result in chronic pain, impaired mobility, pulmonary
dysfunction, a decrease in overall quality of life and early mortality.
Balloon
kyphophasty involves the percutaneous placement of an orthopaedic balloon inside
the fractured vertebral body.
The balloon is inflated, elevating the vertebral
endplates and creating a cavity. After the balloon is removed, the cavity is filled
with bone cement, usually polymethylmethacrylate, thereby stabilising the fracture
which facilitates immediate mobility.
Although more than 50 000 patients have apparently been treated world wide, and
the technique is also available locally, published experience is limited and a recent
review could only document two uncontrolled prospective studies and a number of
case reports. Significant pain relief and improved mobility was apparent within 1-2
days in up to 80% of patients. Complications appear to be uncommon, and were
more prevalent when the bone cement was directly injected into a vertebral body
without first creating a balloon cavity, but include leakage of cement into the
paravertebral tissue, compression of spine nerve roots and pulmonary embolism.
Only patients with severe pain and loss of mobility that has not responded to
conventional therapy should be considered.
Timing of the procedure remains
controversial, and while some advocate kyphophasty within the first two weeks
following a fracture, others suggest conservative treatment for at least 6 weeks.
The latter certainly seems more rational. Other causes of pain must be excluded
and only recent fractures are amenable to kyphophasty.
Totally compressed
vertebrae cannot be reduced, and it has been suggested that the affected vertebra
should retain at least one third of its original height for the procedure to be
successful. CT, MRI or isotope bone scans are employed to select those most likely
to benefit from vertebroplasty.
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Balloon kyphophasty appears to be a safe and effective treatment to stabilise acute
vertebral fractures, reduce pain, restore the bony anatomy and effect early
mobilisation. No evidence-based data on the long-term effects of this procedure,
are however available, in particular the incidence of new vertebral fracture in the
vicinity of the cemented vertebra.
Further randomised, controlled studies are
required before this technique can be recommended for the routine treatment of the
acute vertebral fracture syndrome.
Recommended further reading
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Osteoporosis Prevention, Diagnosis and
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Seeman C. Pathogenesis of bone fragility in women and men. Lancet 2002; 359:
1841-50.
Chesnut CH III, Rosen CJ for the Bone Quality Discussion Group. Reconsidering the
effects of antiresorptive therapies in reducing osteoporotic fracture. J Bone Miner
Res 2001; 16(12): 2163-72.
Hough FS. Population differences in parameters of bone and mineral metabolism –
the African fracture paradox. S Afr J Clin Nutr 2003; 16: 76-79.
Bone HG, Hosking D, Devogelaer JP et al. Ten years’ experience with alendronate
for osteoporosis in postmenopausal women. N Engl J Med 2004; 350: 1189-1199.
Ascott-Evans BH, Guanabens N, Kivinen S et al. Alendronate prevents loss of bone
density associated with discontinuation of hormone replacement therapy: a
randomised controlled trial. Arch Intern Med 2003; 163: 789-94.
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Evio S. Effects of alendronate and HRT, alone and in combination, on bone mass
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The Women’s Health Initiative Stearing Committee. Effects of conjugated equine
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Orwoll ES, Scheele WH, Paul S et al. The effect of teriparatide [human parathyroid
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Meunier PJ, Slosman DO, Delmas PD et al.
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35: 459-68.
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vertebral fractures. Q J Med 2004; 97: 63-74.
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Lin JT, Lane JM. Nonmedical management of osteoporosis. Curr Opin Rheumatol
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vertebroplasty. Manag Care 2000; 9: 56-60.
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